Fused phenanthridines: Domino cyclization of 1,6-diynes with bromo(iso)quinoline

Article abstract of DOI:10.1002/asia.201000692

An offer you can't re-fused: The first examples of a convenient domino synthesis of 7,11-diphenyl-9,10-dihydro-8H-cyclopentaphenanthridine derivatives, such as 3, by the domino palladium-catalyzed cyclization reactions of simple 1,6-diynes with bromo(iso)

Full text of DOI:10.1002/asia.201000692

DOI: 10.1002/asia.201000692
Fused Phenanthridines: Domino Cyclization of 1,6-Diynes with
Bromo(iso)quinoline
AHCTUNGTRENNUNG
Yimin Hu,* Yongjie Sun, Jiping Hu, Tao Zhu, Tao Yu, and Quansheng Zhao[a]
Fused phenanthridines are an important class of heterocy-
cles that show a broad range of biological and pharmaceuti-
cal activity.[1] These structural motifs are found in a plethora
of different natural products (Scheme 1).[2] Molecules con-
ACHTUNGTREN[NUNG 1,2-f]phenanthridine derivatives that exhibit a reversible
“lockable molecular switch”/ring-opening-cyclization pro-
cess. Lautens and co-workers have reported a powerful
strategy for the synthesis of diversely substituted phenan-
thridines and benzo[c]phenanthridines involving a sequence
of domino ortho-functionalization with palladium-catalyzed
cross-coupling processes.[6] Much effort has been invested in
synthesizing the derivatives of these phenanthridines to
deduce structure–activity relationships and discover new an-
alogues with improved properties.[7–9] Notably, Yu and co-
workers reported the first example of directed transition-
À
metal-catalyzed C H functionalizations of a pyridine ring at
the 3- or 4-position.[10] Our group has also employed a
domino strategy to devise alternative processes for the effi-
cient construction of benzocyclo[penta- to octa-]isoindole.[11]
À
We envisioned a C H activation/cross-coupling approach
toward the synthesis of diversely polycyclic phenanthridine
derivatives (Scheme 1). This cascade series consists of inter-
and intramolecular Heck reactions and a subsequent regio-
À
selective direct arylation by C H activation of the quinoline
Scheme 1. Examples of natural products containing phenanthridine alka-
loids and retrosynthetic analysis of fused phenanthridines.
ring at the 2- or 4-positions. Herein, we report the palladi-
um-catalyzed domino reactions of dimethyl 2,2-bis(3-phenyl-
prop-2-ynyl)malonate (1a), diethyl 2,2-bis(3-phenylprop-2-
ynyl)malonate (1b), 1-ethyl 3-methyl 2,2-bis(3-phenylprop-
2-ynyl)malonate (1c), dimethyl 2,2-bis(3-(4-chlorophenyl)-
prop-2-ynyl)malonate (1d), diethyl 2,2-bis(3-(4-chlorophe-
nyl)prop-2-ynyl)malonate (1e), 1-ethyl 3-methyl 2,2-bis(3-
(4-chlorophenyl)prop-2-ynyl)malonate (1 f), dimethyl 2,2-
bis(3-p-tolylprop-2-ynyl)malonate (1g), diethyl 2,2-bis(3-p-
tolylprop-2-ynyl)malonate (1h), diethyl 2,2-bis(3-(4-methox-
yphenyl)prop-2-ynyl)malonate (1i), diethyl 2,2-bis(3-(4-fluo-
rophenyl)prop-2-yn-1-yl)malonate (1j), and dimethyl 2,2-
bis(3-(4-fluorophenyl)prop-2-yn-1-yl)malonate (1k) with 3-
taining phenanthridine are the subject of considerable inter-
est as potent antitumor, antimicrobial, and antiviral agents.[3]
Therefore, numerous synthetic strategies for the preparation
of these scaffolds have been developed.[4] Recently, Cronin
and co-workers[5] developed a new C C bond-forming annu-
À
lation reaction leading to a class of 2,3-dihydro-12H-pyrrolo-
[a] Prof. Dr. Y. Hu, Y. Sun, J. Hu, T. Zhu, T. Yu, Q. Zhao
Laboratory of Functional Molecular Solids
Ministry of Education
bromo
ACHTUNGTREN(NUGN iso)quinoline or 3-bromopyridine, in the direct, effi-
Anhui Key Laboratory of Molecular-Based Materials
School of Chemistry and Materials Science
Anhui Normal University
Wuhu, Anhui 241000 (China)
Fax : (+86)553-388-3517
cient, and economic construction of phenanthridine and
À
À
quinoline through both C C bond coupling and C H bond
activation. Optimization of the reaction conditions was per-
formed using diethyl 2,2-bis(3-(4-chlorophenyl)prop-2-ynyl)-
malonate (1e) and 3-bromoquinoline (Table 1). Reaction of
1e with 3-bromoquinoline in N,N-dimethylformamide
E-mail: yiminhu@mail.ahnu.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201000692.
Chem. Asian J. 2011, 6, 797 – 800
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
797

COMMUNICATION
Table 1. Palladium-catalyzed one-pot cascade reaction.
phenyl-8H-cyclopenta[j]phenanthridine compounds were
readily isolated in good to excellent yields, except in the
case of 5c or 5j, when 1,7-diphenylhepta-1,6-diyne with a
variety of substituted groups was employed. The substituted
groups could be methoxycarbonyl, ethoxycarbonyl, or para-
substituted groups on the benzene ring (chloro, fluoro,
methyl and methoxyl). Using 3-bromoquinoline with diyne
subatrates (a-k), the reaction affords 7,11-diphenyl-9,10-di-
hydro-8H-cyclopenta[j]phenanthridine
3a+4a,
3b+4b,
3d+4d, and 3e+4e, respectively, in yields beyond 81%.
The yields of compound (3a+4a) and (3d+4d) were the
highest at 89%. Simultaneously, when 3-bromo-
AHCTUNGTREG(NNNU iso)quinoline was used in the reaction with c, f–k, the de-
sired phenanthridines were obtained in good yields ranging
from 62–78% (3c, 3 f, 4g, 3i, 3j, 3k and 6b). The reaction
of 3-bromoquinoline with diyne having a methoxycarbonyl
or ethoxycarbonyl group (4a, 4b, 4d and 4e) gave much
lower yields of the products than that of 4a, 4b, 4d, and 4e.
Note that the yield of compound 4g was highest in all deox-
ycarbonyl decomposition[12] of the desired products at 65%.
Interestingly, compound 5c and 5j are low (15% and 18%),
but this is a novel cyclopenta[b]acridine. To test this idea, 3-
bromoisoquinoline was employed to give the single com-
pound 6b (75%). Lastly, with these conditions in hand, the
generality of the cyclization has been studied using 3-bromo-
pyridine to take the place of 3-bromoquinoline. Results
showed that the deoxycarbonyl cyclopenta[g]isoquinolines
7a and 7d give moderate yields 68% and 67%, respectively.
The structures of all of the resulting fused phenanthridine
compounds were confirmed by various spectroscopic tech-
Entry
[Pd] [mol%]
(OAc)2]/PPh3
Base
(equiv)
Solvent
t
T
Yield [%]
[h] [8C] 3e 4e
1
2
3
4
5
6
7
8
9
[Pd
[Pd
[Pd
[Pd
[Pd
[Pd
[Pd
[Pd
[Pd
G
nBu3N (2) MeCN
nBu3N (2) toluene 10 120
nBu3N (2) DMF 11 100 trace
9
110
–
–
(2:4)
(2:4)
(2:4)
(2:4)
(2:4)
(1:2)
(2:4)
(2:4)
(2:4)
G
15 trace
E
–
14
30
12
25
–
N
nBu3N (2) DMF 11 110
nBu3N (2) DMF 16 120
nBu3N (2) DMF 16 120
nBu3N (2) DMF 14 120
41
59
49
64
R
N
G
T
A
NaHCO3
(2)
DMF 14 120 trace
–
10
11
G
19
25
7
6
12
[Pd
G
nBu3N (2) DMF 14 120
24
8
(DMF) in the presence of a catalytic amount of Pd
at 1208C for 14 hours produced diethyl 7,11-bis(4-chloro-
phenyl)-8H-cyclopenta[j]phenanthridine-9,9(10H)-dicarbox-
ACHTUNGERTN(NUNG OAc)2
AHCTUNGTRENNUNG
ylate (3e) and ethyl 7,11-bis(4-chlorophenyl)-9,10-dihydro-
8H-cyclopenta[j]phenanthridine-9-carboxylate (4e) in 89%
yield. The output of the multi-cascade route to product 3e
was found to be greatly affected by reaction temperature
(Table 1, entries 1–4), the additive base (Table 1, entries 8, 9,
11), the catalytic system (Table 1, entries 10–12), and by the
solvent used in the reaction (Table 1, entries 1–2). Thus, the
following optimized reaction conditions were selected for
carrying out the following studies: diyne (1 equiv) was react-
ed with 3-bromoquinoline (1.2 equiv) in the presence of
2 mol% palladium(II) catalyst and 4 mol% Ph3P with
nBu3N (2 equiv) as an additive in N,N-dimethylformamide
at 1208C.
Figure 1. Molecular structure of compound 3e. Ellipsiods are drawn at
30% probability. Selected bond lengths (ꢁ) and angles (8) C7–C13
1.435(6), C8–C10 1.434(7), C10–C11 1.384(6), C11–C12 1.394(6), C12–
C13 1.391(6), C7-C8-C10 122.3(5), C8-C10-C11 117.5(4), C10-C11-C12
120.2(5), C11-C12-C13 123.4(5), C12-C13-C7 117.8(4).
Illustrative examples of the scope of the cascade reaction
are shown in Table 2. Various diynes and 3-bromo-
ACHTUNGTRENNUNG
798
www.chemasianj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2011, 6, 797 – 800

Y. Hu et al.
Table 2. The palladium-catalyzed one-pot formation of fused phenanthridines.[a]
In conclusion, we have devel-
oped a practical and efficient
domino method for the prepa-
ration of diversely fused phe-
nanthridines from readily avail-
able precursors through the
À
multistep C C bond-formation
À
and the C H activation of the
quinoline or isoquinoline ring.
This series produces diphenyl-
cyclopentaphenanthridine de-
rivatives in moderate to very
good yields and excellent regio-
selectivities. This methodology
will certainly aid the effort to
generate more-interesting struc-
tures for use in biological stud-
ies. Further investigation to un-
derstand this catalytic transfor-
mation, evaluation of the pro-
cess with a broader scope of
substrates, and the synthesis of
more-complex p-system hetero-
cycles are underway.
Entry
E1
E2
R
Yield [%][b]
3a
3b
3c
3d
3e
3 f
3h
3i
CO2Me
CO2Et
COMe
CO2Me
CO2Et
COMe
CO2Et
CO2Et
CO2Et
CO2Me
CO2Me
CO2Et
CO2Me
CO2Et
CO2Me
COMe
CO2Et
CO2Et
CO2Me
CO2Me
CO2Me
CO2Et
CO2Et
CO2Me
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Me
–
–
–
–
52
61
62
55
64
78
69
62
65
63
27
23
26
25
65
15
18
75
68
67
Cl
Cl
Cl
Me
OMe
F
F
–
–
Cl
Cl
Me
–
F
–
Experimental Section
3j
Typical Procedure for the Palladium-
Catalyzed Domino Reaction of 1,6-
3k
4a
4b
4d
4e
4g
5c
5j
Diynes with Bromo
ACHTUNGTREN(NGNU iso)quinoline
–
–
–
–
Diyne 1 f (1.0 equiv), 3-bromoquino-
line 2a (1.2 equiv), Pd(OAc)2 (2
ACHTUNGTRENNUNG
mol%), and PPh3 (4 mol%) were
added to the degassed solution of
nBu3N (2 equiv) in N,N-dimethylfor-
mamide (DMF; 5 mL). and the mix-
ture was stirred at room temperature
for 40 min then heated at 115–1208C
for 18 h. The reaction mixture was
cooled, quenched with water, and ex-
tracted with EtOAc (3ꢂ5 mL). The
combined organic layers were washed
with hydrochloric acid (5%), aqueous
sodium carbonate (5%), and saturated
aqueous sodium chloride solution.
CO2Et
CO2Et
CO2Et
–
6b
7a
7d
–
Cl
–
[a] Reaction conditions: 1 (1.0 equiv), bromoACTHNUGTRENNUG(iso)quinoline (1.2 equiv), PdACHTUNGTRENN(UNG OAc)2 (2 mol%), PPh3 (4 mol%),
nBu3N (2 equiv), DMF 10 mL, 115–1208C, 14 h. [b] Yield of isolated product after column chromatography on
silica gel.
niques (1H and 13C NMR spectroscopy, and UV/Vis, IR, and
After separation, the organic layer was dried over anhydrous MgSO4 and
concentrated under reduced pressure. Flash chromatography on silica gel
(eluent: petroleum ether/ethyl acetate=6:1) afforded 3 f (78%) as a
HRMS). The molecular structure and relative configuration
of 3e was unambiguously confirmed by X-ray diffraction
(Figure 1).[13] Further details are provided in the Supporting
Information.
Simplified catalytic cycle mechanisms for the selective for-
mation of polycyclic phenanthridines were proposed in
1
yellow powder; 431 mg (78% yield); m.p. 224–2258C; Rf =0.36; H NMR
À
À
(300 MHz, CDCl3): d=9.03 (s, 1H, Ar H), 8.08 (d, 1H, J=7.5 Hz, Ar
À
À
H), 7.57 (s, 6H, Ar H), 7.38 (d, 2H, J=7.8 Hz, Ar H), 7.32 (d, 2H, J=
À
À
7.2 Hz, Ar H), 7.19 (d, 1H, J=6.9 Hz, Ar H), 4.18 (q, 2H, J=6.9 Hz,
À
À
CH3CHH O ), 3.49 (s, 2H, CH2), 3.38 (s, 2H, CH2), 2.15 (s, 3H,
CH3CO), 1.23 ppm (t, J=6.9 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3):
d=201.9, 171.7, 151.4, 145.3, 143.9, 139.9, 138.3, 135.9, 135.4, 134.2, 133.9,
133.6, 131.3, 131.2, 130.6, 130.1, 129.0, 128.0, 126.6, 125.9, 125.3, 124.0,
66.2, 62.1, 39.8, 38.7, 26.1, 14.0 ppm; UV/Vis (CH3CN): 261 nm; FT-IR
(KBr): n˜max =1739, 1710, 1244, 1093, 1014, 817, 773, 524 cmÀ1; HRMS
(ESI): m/z [M+H]+ calcd. for C33H26Cl2NO3: 554.1290; found: 554.1303.
Scheme 2. Oxidative addition of the bromoACTHNUGRTENUNG(iso)quinoline
(2a) would afford aryl-palladium intermediate A which can
subsequently undergo carbopalladation with the diyne
moiety (1) to yield intermediate B, which then reacts
À
through a carbopalladation reaction with the carbon carbon
double bond and s-bond metathesis onto the aryl group via
intermediate C. Proton-abstraction[14] by the base affords
polycyclic phenanthridine 3.
Chem. Asian J. 2011, 6, 797 – 800
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
799

Domino Cyclization of 1,6-Diynes to Afford Fused Phenanthridines
COMMUNICATION
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Scheme 2. Proposed catalytic cycle.
Acknowledgements
The authors thank the National Science Foundation of China (21072003,
20872002) for financial support. The authors also thank Ms. Yun Wei and
Prof. Xiaolong Mu for X-ray crystallography.
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[13] Crystal structure determination: C34H27Cl2NO4 3e, M=584.47, tri-
clinic, space group P-1, a=8.996(2), b=26.334(6), c=12.674(3) ꢁ,
U=2853.4(1) ꢁ3, T=293 K, Z=4, 2023 reflections measured, 6597
unique (Rint =0.0819) which were used in all calculations. The final
wR(F2) was 0.1778 (all data). CCDC 792043 contains the supplemen-
tary crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
À
Keywords: C H activation · cyclization · domino reactions ·
fused phenanthridines · palladium
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Received: September 24, 2010
Published online: January 11, 2011
800
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Chem. Asian J. 2011, 6, 797 – 800